Immunodeficient Fcgr1 Knockout Mice Extend Human IgG Half-Life
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Solution Overview
Problem
Existing mouse models for testing human IgG antibody pharmacokinetics and efficacy are limited due to rapid clearance of human IgGs by mouse FcγR1 receptors, which shortens the half-life of antibodies and hinders accurate assessment of therapeutic efficacy against human diseases, particularly cancers.
Innovation Solution
Development of an immunodeficient Fcgr1 knockout mouse model that lacks the FcγR1 receptor, combined with a human IL-15 transgene, to enhance the circulating half-life of human IgGs and support the engraftment of human hematopoietic stem cells, allowing for more accurate pharmacokinetic and efficacy studies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If mouse FcγR1 receptors are present in existing mouse models, then immune signaling activation occurs, but human IgG antibody half-life is rapidly reduced due to clearance
Solution Approach 1:
The patent removes the harmful FcγR1 receptor component from the mouse model system by creating an Fcgr1 knockout mouse. This extraction eliminates the rapid clearance mechanism that otherwise would degrade human IgG antibodies, thereby extending antibody half-life and enabling accurate pharmacokinetic studies.
Solution Approach 2:
The patent converts the normally harmful rapid clearance function of FcγR1 into a beneficial feature by selectively eliminating this receptor while preserving other immune functions. The knockout transforms what would be a confounding variable into a controlled advantage for antibody stability.
2Measurement precision
If standard immunodeficient mouse models are used, then engraftment of human cells is possible, but accurate assessment of therapeutic efficacy is hindered due to antibody clearance
Solution Approach 1:
The patent extracts the specific FcγR1 receptor that causes premature antibody clearance, creating a mouse model where human IgG antibodies circulate at therapeutic levels for extended periods. This enables accurate measurement of true therapeutic efficacy without the confounding effect of rapid clearance.
Solution Approach 2:
The patent changes the immunological parameter of the mouse model by knocking out the Fcgr1 gene, thereby altering the pharmacokinetic parameters of human antibodies in the system. This parameter change extends antibody half-life from hours to days, enabling meaningful efficacy assessments.
3Quantity of substance
If FcγR1 receptor function is maintained, then immune cell signaling is activated, but human IgG levels remain low due to internalization and degradation
Solution Approach 1:
The patent removes the FcγR1 receptor that mediates internalization and degradation of human IgG antibodies. Without this receptor, antibodies are not internalized and degraded, allowing them to maintain therapeutic circulating levels necessary for effective cancer therapy.
Solution Approach 2:
The patent converts the harmful internalization-degradation pathway into a beneficial state by eliminating the FcγR1 receptor. This transformation allows human IgG antibodies to persist in circulation at high levels, turning a normally destructive process into a stable therapeutic environment.
Data Source
AI summary
The present disclosure provides, in some aspects, an immunodeficient NOD-Fcgr1null mouse that may be used to measure human IgG antibody pharmacokinetics and activity, produce human IgG antibodies, and model human disease treatment.